Toxic metabolites, production

Toxicity is a major cause for the withdrawal of drugs from the market and it is a major concern for pharmaceutical researchers. Reactive metabolism is certainly a very hot topic within the whole approach to drug metabolism. The downstream consequences of not identifying reactive metabolites may be financially catastrophic. There is an increasing drive to have early prediction of the metabolic fate and interactions of candidate drug molecules. Factors such as metabolic stability, toxic metabolite production, and P450 inhibition and induction are all routinely monitored to prevent compounds with poor pharmacokinetic properties from progressing forward onto clinical trials. 

Figures 17.1 and 17.2(a) used either a scatter diagram or histogram to expose the non-normal distribution of toxic metabolite production and warned us that the direct application of a /-test was hazardous, whereas Figure 17.2(b) provided reassurance that log transformation had pretty much fixed the problem. Just by looking at Figure 17.4, we knew immediately that there was little point even trying to transform the analgesic effectiveness scores to normality we were better off just going straight to a non-parametric test.

The increase in cell production due to UF is shown in Figure 3.103.76 Clostridium histolyticum is cultivated in batch and continuous fermentors. In the batch system, the organism approaches a stationary phase at about the twelfth hour due to toxic metabolite production. In the continuous fermentor, fresh substrate is fed continuously and the toxic products are continuously removed enabling growth to continue well past the fortieth hour. Likewise, the enzyme production from this fermentor is enhanced (see Figure... 

The signiflcance of toxic metabolites is important in diverse metabolic situations (a) when a pathway results in the synthesis of a toxic or inhibitory metabolite, and (b) when pathways for the metabolism of two (or more) analogous substrates supplied simultaneously are incompatible due to the production of a toxic metabolite by one of the substrates. A number of examples are provided to illustrate these possibilities that have achieved considerable attention in the context of the biodegradation of chlorinated aromatic compounds (further discussion is given in Chapter 9, Part 1) ... 

Williams, J.G. and Hallett, M.B. (1989).Effect of sulphasalazine and its active metabolite, 5-aminosalicylic acid, on toxic oxygen metabolite production by neutrophils. Gut 30, 1581-1587. 

Ethylenethiourea (ETU) is a toxic decomposition product/metabolite of alky-lenebis(dithiocarbamates). This compound could be generated during processing of treated crops at elevated temperature. Different chromatographic methods to determine the residue levels of ETU have been published. After extraction with methanol, clean-up on a Gas-Chrom S/alumina column and derivatization (alkylation) with bro-mobutane, ETU residues can be determined by GC with a flame photometric detector in the sulfur mode. Alternatively, ETU residues can also be determined by an HPLC method with UV detection at 240 nm or by liquid chromatography/mass spectrometry (LC/MS) or liquid chromatography/tandem mass spectrometry (LC/MS/MS) (molecular ion m/z 103). ... 

Environmental agents that influence microsomal reactions will influence hexachloroethane toxicity. The production of tetrachloroethene as a metabolite is increased by agents like phenobarbital that induce certain cytochrome P-450 isozymes (Nastainczyk et al. 1982a Thompson et al. 1984). Exposure to food material or other xenobiotics that influence the availability of mixed function oxidase enzymes and/or cofactors will change the reaction rate and end products of hexachloroethane metabolism and thus influence its toxicity. 

Vacuoles (70-78) are membrane-bound regions of the cell filled with cell sap. Vacuoles are surrounded by a tonoplast (vacuolar membranes) and are diverse with distinct functions. Most investigators believe that lysosomes and the plant vacuoles are the same. Vacuoles develop turgor pressure and maintain tissue rigidity. They are storage components for various metabolites such as reserve proteins in seeds and malic acid in crassulacean acid metabolism (CAM) plants. Vacuoles canremove toxic secondary products and are the sites of pigment deposition. 

In order to study simultaneously the behaviour of parent priority surfactants and their degradation products, it is essential to have accurate and sensitive analytical methods that enable the determination of the low concentrations generally occurring in the aquatic environment. As a result of an exhaustive review of the analytical methods used for the quantification within the framework of the three-year research project Priority surfactants and their toxic metabolites in wastewater effluents An integrated study (PRISTINE), it is concluded that the most appropriate procedure for this purpose is high-performance (HP) LC in reversed phase (RP), associated with preliminary techniques of concentration and purification by solid phase extraction (SPE). However, the complex mixtures of metabolites and a lack of reference standards currently limit the applicability of HPLC with UV- or fluorescence (FL-) detection methods. 

We also note that some 2,2-disubstituted oxiranes have toxicological significance, as exemplified by 2,2-dimethyloxirane (2-methyl-l, 2-epoxypropane, 10.43, R = Me). This compound is the toxic metabolite of 2-methyl-prop-1-ene (isobutene), a gaseous alkene widely used as a monomer in the industrial production of adhesives, plastics, and other polymers. Interestingly, detoxification of this epoxide catalyzed by liver epoxide hydrolase was high in the human, intermediate in the rat, and low in the mouse [125], These activities were inversely correlated with the epoxide levels measured in vitro in liver tissue of these species. 

Direct organ toxicity. Some substances may directly damage cells of a particular organ or system, either because they or their metabolites are specifically toxic to these cells, or because they are concentrated in one area, e.g. the renal fluoride ion toxicity of methoxyflurane, or the liver damage that occurs in paracetamol overdose because of a toxic intermediate product binding to hepatocytes. Secondary effects. Some effects are only indirectly related to the action of the drug, e.g. vitamin deficiency in patients whose gut flora have been modified by broad-spectrum antibiotics. 

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